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Evaluation of De Ritis ratio in liver-associated diseases

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 Research Article

Evaluation of De Ritis ratio in liver-associated diseases

Kumari Shipra Parmar1, Ganesh Kumar Singh2, Govind Prasad Gupta3, Tanuja Pathak4, Sandeep Nayak5
Department of Biochemistry, M. B. Kedia Dental College, Tribhuvan University, Birgunj, Nepal.
1

Department of Microbiology, Nobel Medical College, Kathmandu University, Biratnagar, Nepal.

2

3
Department of Microbiology, M. B. Kedia Dental College, Tribhuvan University, Birgunj, Nepal.
4
Department of Pharmacology, M. B. Kedia Dental College, Tribhuvan University, Birgunj, Nepal.
5
Department of Preventive and Community Dentistry, M. B. Kedia Dental College, Tribhuvan University, Birgunj, Nepal.
Correspondence to: Kumari Shipra Parmar, E-mail: spbiochem02@gmail.com

Received December 24, 2015. Accepted January 4, 2016

Abstract

Background: Liver diseases are one of the common disorders encountered in clinical practice. Investigations in liver-
associated diseases are used to detect type of hepatic abnormality, to measure its severity, to define its structural effect
on the liver, to find out etiology of disorder, to assess prognosis, and to evaluate therapy. One should aim at a diagnosis
with simple and possibly noninvasive means, avoiding extensive examinations. De Ritis ratio (the ratio of serum aspartate
aminotransferase to serum alanine aminotransferase) has been proposed a valuable diagnostic marker to screen liver
disorder.
Objective: To assess the significance of De Ritis ratio as a diagnostic marker in population of hepatic disorder.
Materials and Method: This is a retrospective study performed on records of 102 patients with liver diseases who were
treated at the out-patient clinic or admitted to Nobel Medical College, Biratnagar, Nepal, between June 15, 2015 and July
15, 2015. De Ritis ratio of all the patients were calculated from documented biochemical tests of AST and ALT. De Ritis
ratio and demographic profile of all the patients were analyzed by independent t -test and one-way ANOVA using software
SPSS 20 version.
Results: De Ritis ratio was significantly decreased (p < 0.05) in viral hepatitis (0.8006 ± 0.14811) than the control group
(1.0934 ± 0.13508) and markedly increased (p = 0.000) in alcoholic liver disorder. Similarly, It is significantly increased
(p < 0.05) in nonalcoholic fatty liver disorder (1.2204 ± 0.17954), whereas insignificantly increased (p = 0.408) in cholestasis
(1.1378 ± 0.18045).
Conclusion: De Ritis ratio can be used as a prognostic marker of liver disorder and can be considered as a noninvasive,
cost–effective means of screening liver diseases.
KEY WORDS: De Ritis ratio, alcoholic liver disorder, viral hepatitis, nonalcoholic, fatty liver disorder, cholestasis

Introduction multifold functions such as metabolism of carbohydrates, pro-

teins and lipids; synthesis and excretion of bile; synthesis of
The liver is the largest organ in the body weighing about several plasma proteins such as albumin, fibrinogen, and pro-
1,400–1,600 g in males and 1,200–1,400 g in females performing thrombin; storage of vitamins (A, D, and B12) and iron; and
detoxification of xenobiotic. Hepatic injury is therefore associ-
ated with distortion of all these functions.[1,2]
Access this article online Liver diseases are classified into two categories—hepato-
Website: http://www.ijmsph.com Quick Response Code: cellular and cholestatic. In hepatocellular diseases, features
of liver injury, inflammation, and necrosis predominate while
DOI: 10.5455/ijmsph.2016.24122015322
in cholestatic diseases, features of inhibition of bile flow
predominate.[2] Evaluation of patients with liver disease should
be directed at establishing the etiologic diagnosis, estimating
the disease severity (grading) and establishing the disease
stage. Several biochemical tests are useful in the evaluation

International Journal of Medical Science and Public Health Online 2016. © 2016 Kumari Shipra Parmar. This is an Open Access article distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), allowing third parties to copy and redistribute the material in any medium or format
and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.

International Journal of Medical Science and Public Health | 2016 | Vol 5 | Issue 09 (Online First) 1
 Parmar et al.: De Ritis in screening hepatic disorder
and management of patients with hepatic diseases. In view
of multiplicity and complexity of the liver functions, a battery
of liver function tests (LFTs) are employed for accurate diag-
nosis, which include the aminotransferases, alkaline phos-
phatase, bilirubin, albumin, and prothrombin time.[2]
Assessment of liver cell injury is done by the estimation
of serum aspartate transaminase or AST (formerly glutamic
oxaloacetic transaminase or SGOT) and serum alanine
transaminase or ALT (formerly glutamic pyruvic transaminase
or SGPT). AST is found in the liver, cardiac muscle, skeletal
muscle, kidney, brain, pancreas, lungs, leukocytes, and
erythrocytes while ALT is found primarily in the liver. These
enzymes are normally released into plasma at a constant
rate due to programmed cell death of hepatocytes but its
permeability is increased when there is damage to liver cell
membrane.[2] Thus, ALT is more specific to hepatic necrosis
in comparison to AST. ALT is present only in liver cytoplasm
while AST is found in both hepatocyte cytoplasm (cAST) and
mitochondria (mAST) with approximately 80% of total AST
activity in human liver contributed by mAST.[3]
The hepatic proportion of AST/ALT is 2.5:1. But half-life
(t1/2) of AST and ALT is 18 and 36 h, respectively; thus, AST is
removed from blood twice as faster compared to ALT resulting
nearly equal levels of AST and ALT in serum in healthy
person. Furthermore, in healthy person, circulating AST in
blood consists mainly of cAST.[3] Any type of liver cell injury
causes increased permeability of AST and ALT and can cause
modest increase in the level of these enzymes. Levels upto
300 U/L are nonspecific, whereas levels >1000 U/L occur
in disorders associated with extensive hepatocellular injury
such as viral hepatitis, ischemic liver injury, and toxin- or
drug-induced liver injury.[2] These conditions are characterized
by extensive loss of hepatic parenchyma.[4] In alcoholic liver
disorder (ALD), the level of AST is rarely >300 U/L and ALT
is slightly increased or normal. These enzymes are not greatly
elevated in cholestatic diseases except during the acute
phase of biliary obstruction.[2]
The ratio of serum activities of AST and ALT was described
by Fernando De Ritis in 1957 and since then it is known as De
Ritis ratio. De Ritis described AST/ALT as useful indicator of
hepatitis and his work was confirmed and further investigated
by Wroblewski.[3] This ratio was originally used to distinguish
aminotransferase elevations of the inflammation type (De Ritis
ratio <0.7) from the necrosis type (De Ritis ratio >0.7).[5]
Although there is considerable overlapping of values within
a given diagnosis, several studies have shown that this ratio
is useful in differential diagnosis and classification of hepatic
disorders. The ratio is particularly useful to differentiate intra-
hepatic >1.5 and extrahepatic <1.4 lesions. This ratio is most
useful when standard AST and ALT assays are used as
recommended by the International Federation of Clinical
Chemistry (IFCC), which is 1.15 normally.[6] For normal indi-
vidual, De Ritis ratio vary from 0.7 to 1.4. In most of the acute
hepatocellular diseases such as acute viral hepatitis and
infectious mononucleosis, the De Ritis ratio is ≤1.[7] Chronic
disorders such as alcoholic liver disease, postnecrotic cirrhosis,
2 International Journal of Medical Science and Public Health | 2016 | Vol 5 | Issue 09 (Online First)
and chronic active hepatitis have De Ritis ratio greater than 1.[6]
De Ritis ratio >2 is suggestive while >3 is highly suggestive of
ALD.[2] A ratio >4 may suggest Wilson disease.[7]
There are many modalities available for imaging the liver,
for example, USG, CT, and MRI. Liver biopsy is the most accu-
rate means of assessing severity and stage of liver damage.[2]
For accurate diagnosis of liver disorder, these techniques are
more sensitive and specific.[1] But these are expensive and
also liver biopsy is an invasive procedure with various com-
plications.[8] De Ritis ratio is a noninvasive, cost–effective test
to diagnose and differentiate liver disorder without causing
any complications to the patient. But there are contradictory
reports on the usefulness of De Ritis ratio in differentiating
various types of liver diseases.
The aim of this study is to estimate De Ritis ratio in patients
with viral hepatitis, ALD, nonalcoholic fatty liver disorder
(NAFLD), and cholestasis.
Materials and Methods
This is a retrospective study. This study was performed on
records of 102 patients with liver diseases who were treated
at the out-patient clinic or admitted to Nobel Medical College,
Biratnagar, Nepal, between June 15, 2015 and July 15, 2015.
Data were collected from patient medical records and the
computerized departmental database. Out of 102 patients,
20 were diagnosed with viral hepatitis, 20 with ALD, 20 with
NAFLD, and 10 with cholestasis. Thirty-two patients were
considered as control whose lab tests and imaging modalities
were normal. Subjects with HIV, muscle disorder, renal disorder,
drug abuse, or drug affecting the liver disease were excluded
from the study. Demographic profile of all the patients were
also recorded and analyzed.
Statistical Analysis
De Ritis ratio of all the patients was calculated. Values and
means of AST, ALT, and De Ritis ratio for control, ALD, viral
hepatitis, NAFLD, and cholestasis were calculated separately
and analyzed using SPSS for windows version 20. Com-
parison of means of variables among different groups was
performed with ANOVA. Comparison of means of De Ritis ratio
between control and individual cases was performed with
independent t test. The p value <0.05 was considered statis-
tically significant.
Results
Out of 102 subjects, 39 were male and 63 were female of
the age group 3–85 years. In control group 23 were females
with mean age 33 and 9 were males with mean age 62. In
ALD group, 12 were females with mean age 37 and 8 were
males with mean age 43. In viral hepatitis group, 12 were
females with mean age 26 and 8 were males with mean age 43.
In NAFLD group, 10 were females with mean age 37 and 10
 Parmar et al.: De Ritis in screening hepatic disorder

Table 1: Male and female patients

Disorder
Control ALD Viral hepatitis NAFLD Cholestasis
Count Count Count Count Count
Female 23 12 12 10 6
Sex
Male 9 8 8 10 4

Table 2: Age and sex distribution in case and control

Disorder
Control ALD Viral hepatitis NAFLD Cholestasis
Mean Min Max Mean Min Max Mean Min Max Mean Min Max Mean Min Max
Age F 33 14 70 37 19 72 26 4 48 37 10 70 28 18 44
Sex M 62 39 84 43 19 56 43 15 78 52 3 85 29 10 60

Table 3: Mean serum levels of AST, ALT, De Ritis ratio in cases and control
Disorder AST (Mean ± Std. Dev.) ALT (Mean ± Std. Dev.) De Ritis ratio (Mean ± Std. Dev.)
Control 28.9688 ± 7.12327 27.3125 ± 9.09249 1.0934 ± .13508
ALD 158.3000 ± 71.28084 78.8500 ± 39.71381 2.1253 ± .84766
Viral hepatitis 74.6500 ± 49.14883 94.4000 ± 59.87214 .8006 ± .14811
NAFLD 105.0500 ± 174.87243 96.1500 ± 174.55998 1.2204 ± .17954
Cholestasis 34.4000 ± 12.13992 31.2000 ± 13.02817 1.1378 ± .18045
P value 0.000 0.011 0.000

were males with mean age 52. In cholestatic group, 6 were
females with mean age 28 and 4 were males with mean age
29 (Figure 1, Tables 1 and 2).
Mean aspartate transaminase levels were markedly incre­
ased in ALD (158.3000 ± 71.28084), viral hepatitis (74.6500 ±
49.14883), NAFLD (105.0500 ± 174.87243), and only mildly
increased in cholestasis patients (34.4000 ± 12.13992) as
compared to control (28.9688 ± 7.12327) (Figure 3).
Mean alanine aminotransferase levels were also markedly
elevated in ALD (78.8500 ± 39.71381), viral hepatitis (94.4000 ±
59.87214), NALD (96.1500 ± 174.55998), and only slightly
elevated in cholestasis patients (31.2000 ± 13.02817) as
compared to control (27.3125 ± 9.09249) [Figure 4].
Mean De Ritis ratio is markedly raised in ALD but decre­
ased in viral hepatitis while slightly increased in patients with
NAFLD and cholestasis. The level was found to be 2.1253 ±
0.84766, 0.8006 ± 0.14811, 1.2204 ± 0.17954, and 1.1378 ±
0.18045 as compared to control 1.0934 ± 0.13508 [Figure 5].
The means of AST, ALT, and De Ritis ratio of control and
cases were compared simultaneously with one-way ANOVA
and the difference was found significant (p = 0.000, 0.011, and
0.000 for AST, ALT, and DE Ritis ratio, respectively) [Table 3].
Mean of De Ritis ratio was compared between control and
each case separately by independent t test. The mean of De
Ritis ratio of control and ALD, viral hepatitis and NAFLD was
found to be significantly different (p = 0.000, 0.000, and 0.005,
respectively) while the comparison of mean of De Ritis ratio
of control and cholestasis was not significantly different
(p = 0.408).
Discussion
Aminotransferases are sensitive indicators of hepatocyte
injury. The pattern of the aminotransferase elevation, that is,
De Ritis ratio can be helpful diagnostically.[3] Viral hepatitis is
a leading cause of virus-associated morbidity and mortality,
affecting millions of people worldwide. In acute viral hepatitis,
ALT is greater than AST. The peak level of aminotransferases
has been found to be 400–4,000 U/L or more. De Ritis was
the first to describe that ALT is usually higher than AST with
the AST/ALT ratio usually well below 1.0 and typically in the
range of 0.5–0.7.[3] Reason behind this has been postulated
that AST includes mAST isozymes and more time is needed
for these isozymes to pass through a second set of mem-
branes to reach plasma in comparison to ALT, which is found
in cytoplasm only.[6] When the inflammatory process of acute
viral hepatitis especially B and C merges into chronic hepatitis,
aminotransferase level falls below 100 U/L and De Ritis ratio
changes to ≥1.[4] Diagnosis of viral hepatitis is based on
serological tests and polymerase chain reaction, which is
expensive and also not available in rural areas of Nepal. Thus,
multifold elevation of transaminases and a low De Ritis ratio
provides an important clue to the etiology of acute hepatitis.
The De Ritis ratio for patients of viral hepatitis in our study was
0.8006 ± 0.14811, which is consistent with the results of De
Ritis et al. (1965) and Hasan et al. (2013).[9,10]
High alcohol consumption is one of the most common
causes of liver disorder. The prevalence of alcohol consump-
tion among Nepalese adults was 67% in 2006.[11] In alcoholic

International Journal of Medical Science and Public Health | 2016 | Vol 5 | Issue 09 (Online First) 3
 Parmar et al.: De Ritis in screening hepatic disorder

Figure 4: Mean of De Ritis in case and control.

Figure 1: Correlation of age and sex with case and control.

Figure 2: Mean AST level in case and control.

Figure 5: ROC curve.

Figure 3: Mean ALT level in case and control. Figure 6: Average AST, ALT, and De Ritis ratio in cases and control.

4 International Journal of Medical Science and Public Health | 2016 | Vol 5 | Issue 09 (Online First)
 Parmar et al.: De Ritis in screening hepatic disorder
hepatitis, AST levels are typically higher than ALT with De Ri-
tis ratio greater than 2.[12] The predominance of AST over ALT
in alcohol-related disorder was first reported by Harinasuta
in 1967.[3] The aminotransferase levels are only moderately
elevated in ALD, and ALT levels may even be normal.[4] Reasons
for this are multifold. Chronic alcoholics are often deficient in
pyridoxal 5’-phosphate (vitamin B6), which is a necessary
coenzyme for both ALT and ALT synthesis. Deficiency of
Vitamin B6 decreases ALT synthesis to a greater extent than
AST synthesis.[13] In addition, alcohol itself induces the synthesis
and release of mAST, thereby increasing the De Ritis ratio.[4]
Next, mAST is found in perivenular area in the liver around
the central vein. In ALD, since more perivenular hepatocytes
are damaged, mAST is elevated and hence De Ritis ratio gets
elevated. This is supported by the finding that normally most
of AST activity in serum is the cytosolic isoenzyme; however,
in alcoholism, mAST is preferentially released. Cohen and
Kaplan evaluated the usefulness of the De Ritis ratio and
suggested its diagnostic value as a predictor of ALD. Our study
also shows De Ritis ratio to be 2.1253 ± 0.84766 (p = 0.000),
which is in accordance with the study of Nyblom et al. (2004)
and Hasan and coworkers (2013).[10,14]. Study by Gurung et al.
in 2013 further extended the correlation of De Ritis and ALD
and suggested that De Ritis is indicative of severity of liver
damage due to alcohol.[15]
NAFLD is one of the most frequent complications of obesity.
The prevalence of NAFLD is over 20% in developed coun-
tries and nearly 10% in developing countries. Pathogenesis of
NAFLD is related to obesity, caused by increased lipogenesis
in liver. Most of these patients have type 2 diabetes or hyper-
lipidemia. Other causes of NAFLD are viral hepatitis, medica-
tions, toxins, surgical procedures, protein-energy malnutrition,
and inborn errors of metabolism.[3] NAFLD causes elevation
of serum aminotransferases and liver disease, which could
end up in fibrosis, cirrhosis, and eventually hepatic carcinoma.
Both AST and ALT increase with body weight and this is more
prominent for ALT rather than AST. This is associated with
insulin resistance and is considered as the hepatic manifesta-
tion of the metabolic syndrome. In several studies, ALT elevation
has correlated with the hepatic fat on imaging.[6] De Ritis ratio
<0.8 has a 93% predictive value of little or no fibrosis on biopsy
while >0.8 increases the likelihood of advanced fibrosis or
cirrhosis on biopsy. The finding of De Ritis ratio 1.2204 ±
0.17954 (p = 0.005) in patients with NAFLD in our study
suggests the presence of fibrosis or cirrhosis, which is not
consistent with the study done by Mittal in 2011 at Manipal
College of Medical Sciences, Pokhara, Nepal.[16] The disparity
of result because the patient at Manipal Medical College may
be in initial stage of NAFLD (steatosis), before advancement
of fibrosis and cirrhosis.
In cholestasis, there is accumulation of bile in cells and
biliary passages due to reduction in bile flow. The defect in
excretion may be within the biliary canaliculi of the hepatocyte
and in the microscopic bile ducts (intrahepatic cholestasis) or
there may be mechanical obstruction to the extrahepatic
biliary excretory apparatus (extrahepatic cholestasis).[1] Serum
International Journal of Medical Science and Public Health | 2016 | Vol 5 | Issue 09 (Online First)
aminotransferases are not highly increased in this disorder.[2]
De Ritis ratio of ≥1.5 suggests intrahepatic cholestasis while
values ≤1.5 suggest an extrahepatic process.[6] Our study
have shown slight increment of De Ritis ratio (p = 0.408) in
comparison to control, which is consistent with the investiga-
tions by De Ritis et al. (1965).[9]
Conclusion
The pattern of elevation of aminotransferases, that is,
De Ritis ratio is lesser than 1 in viral hepatitis, <1 to 1.5 in
NAFLD and cholestasis, and >2 in ALD. Hence, the level of
aminotransferases along with De Ritis ratio can be a useful
biochemical test to screen the population of liver disorder,
which is noninvasive and cost–effective method in less affluent,
undeveloped region where people cannot afford battery of liver
function test.
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